The advantages of transdermal drug delivery over other methods of drug administration are well recognized. Working alone, most drugs do not sufficiently permeate the skin to provide therapeutic levels of drug delivery. The skin, especially the outer layer (stratum corneum), provides a formidable barrier to the penetration of most substances. To overcome the skin's natural protective barrier, topical drug formulations typically include a skin penetration enhancer. Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilizers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin. Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitizing, or damaging skin. Furthermore, ideal penetration enhancers should not adversely affect the stability of the active drug, the physical stability of the dosage form (e.g. cream or gel), or the cosmetic quality of the topical composition.
A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Ghosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997), which surveys the use and testing of various skin penetration enhancers.
Of the many groups of compounds being evaluated, several alkyl (N,N-disubstituted amino alkanoate) esters have shown promise as penetration enhancers. Of the alkyl (N,N-disubstituted amino alkanoate) esters, dodecyl 2-(N,N dimethylamino)-propionate (DDAIP) has shown particular promise because of its confirmed biodegradability. For a discussion of the penetration enhancing properties of DDAIP see Buyuktimkin et al., Alkyl N,N-Disubstituted-Amino Acetates in Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995).
DDAIP, which may also be referred to as dodecyl 2-methyl-2-(N,N-dimethyl amino) acetate, is an effective skin penetration enhancer for a wide variety of medicaments and has the following chemical formula: ##STR1## DDAIP is a liquid at room temperature and as such is not easy to purify. DDAIP is not soluble in water, but is miscible with most organic solvents. Table I, below, contains a list of other reported attributes of DDAIP.
TABLE I ______________________________________ Physical Properties Of DDAIP ______________________________________ Molecular Weight 285.47 CAS Number 149196-89-4 Physical form Clear colorless liquid Freezing point -17.5.degree. C. Boiling point 142-144.degree. C./0.1 mmHG Viscosity 7.32 centiStokes at 23.degree. C. Refractive Index (nD) 1.4435 at 24.5.degree. C. Specific gravity (D.sub.23) 0.85 ______________________________________
What is needed is a form of DDAIP that can be readily purified and adapted for use in the variety of dosage forms used for transdermal delivery. Furthermore, what is needed is a reliable cost effective method of manufacturing DDAIP.